Particulate compositions

ABSTRACT

The present invention is a method for forming a composition in solid particulate form from a mixture of constituents, at least one of which is a liquid, the method comprising forming said composition from a mixture of constituents comprising a lipophilic liquid, a hydrophilic solid dispersant, and a solid particulating agent.

This application claims the priority of U.S. Provisional Application No.60/343,142, filed Dec. 20, 2001, which is incorporated herein byreference.

SUMMARY OF THE INVENTION

In accordance with this invention, there are provided solid particulateswhich are formed from a lipophilic liquid, a hydrophilic soliddispersant, and a solid particulating agent. Particulates disclosedherein are characterized by their liquid-retention properties, that is,the liquid constituent of the particulates does not exude from theparticulates when they are subjected to pressure, for example, pressurewhich is sufficient to form a cohesive tablet from a powder form of theparticulates.

There is provided also in accordance with the present invention, atablet which has a friability of less than about one wt. % and whichcomprises a hydrophilic solid dispersant, a solid particulating agent,and a lipophilic liquid that is dispersed uniformly throughout saidcomposition and is dispersible from said tablet upon contact with anaqueous media within about five minutes. In preferred form thelipophilic liquid is dispersible from the composition within about oneminute after contacting the composition with an aqueous media.

Another aspect of the present invention is the provision of a method forforming a composition in solid form from a mixture of constituentscomprising a lipophilic liquid, a hydrophilic solid dispersant, and asolid particulating agent. In preferred form, the composition is formedby adding the particulating agent to a mixture of the lipophilic liquidand the hydrophilic solid dispersant. Also, in preferred form, thecomposition of the present invention comprises a lipophilic liquid whichis an oil that has bioactive properties, the particulating agent is aningestible oxide, and the hydrophilic solid dispersant is a sugar, apolyhydroxy alcohol, or a polysaccharide.

DETAILED DESCRIPTION OF THE INVENTION

There are a multitude of applications where it is desired to form acomposition which is a solid at room temperature from a mixture ofmaterials in which at least one of the materials is a liquid at roomtemperature. For a number of such applications, it is essential that thenormally liquid constituent of the resulting solid be retained in thesolid composition when it is subjected to pressure. As such, the solidcomposition should have liquid-retention properties.

In some applications, it is essential that the liquid material in thecomposition be dispersed from the solid composition within a relativelyshort time, for example, five minutes after contact with an aqueousmedium, and in such applications, compositions which disperse the liquidmaterial in one minute or less after contact with an aqueous media arepreferred. As such, the solid composition should have alsoliquid-dispersing properties.

One example of the aforementioned types of applications is the provisionof a tablet for oral ingestion in which the tablet comprises a normallyliquid material which has bio-active properties, for example,pharmaceutical activity. Typically, a tablet is formed by compressingand shaping a powdery mixture of the materials comprising the tablet.The present invention can be utilized effectively to form tablets from amixture of materials in which at least one of the materials is normallya liquid at room temperature.

It is believed that the present invention will be used widely inapplications which involve the formation of tablets from a powderymixture of materials which include a liquid material and a materialwhich has bio-active properties. However, the present invention hasbroader applicability and, accordingly, involves the formation of acomposition in the form of solid particulates which are formed from amixture of materials comprising a lipophilic liquid, a hydrophilic soliddispersant, and a solid particulating agent. The term “particulates”refers to discrete particles, for example, pellets, beads, granules, andpowders, the last mentioned preferably having an average particle sizebetween about five and about 300 microns (μm).

The lipophilic liquid for use in the present invention comprises amaterial which is soluble in a non-polar solvent, for example, aliphaticorganic solvents, fats, and oils, and is immiscible or partiallyimmiscible in water, that is, its miscibility in water is not greaterthan about 0.01 wt. % e.g. at 25° C.

Lipophilic liquids suitable for use in the practice of the presentdevelopment can be either a material which itself has desired propertiesor a material which functions as a carrier, for example, a solvent, fora material that has desired properties. The lipophilic liquid can besynthetic or naturally occurring or derived from natural sources.Silicone oils are an example of a class of synthetic materials which canfunction as a solvent or carrier of materials having desired properties.Examples of lipophilic liquids derived from natural sources that canfunction as a carrier or solvent are seed oils, for example, corn oil,and animal source oils, for example liver oil and squalene. Additionalexamples include oils from edible seeds and olive oil.

As mentioned above, it is believed that the present invention will beused widely in applications in which the solid composition has bioactiveproperties, that is, the composition includes one or more ingredientsthat impart to it bioactive properties. The bioactive material for usein the composition of the present invention is any substance which canbe introduced into an animal's biological system via absorption from thegastrointestinal tract of the animal and which, upon absorption, elicitsin the animal a therapeutic, prophylactic, diagnostic, or nutritionalresponse.

Examples of bioactive properties are analgesic activity, anti-oxidantactivity, vitamin supplementation, carminative, local anesthetic,expectorant, anthelmintic and local antiseptic.

For such bioactive applications, the lipophilic liquid comprises abioactive material. The lipophilic liquid itself may have bioactiveproperties or bioactive material may be present as another liquid or asa solid that is dissolved in the lipophilic liquid. For example, thereare naturally occurring oils which comprise a mixture of ingredientsthat include one or more solids that have bioactive properties and thatare dissolved in the oil by an ingredient of the oil which is a solventfor the bioactive material. Bioactive lipophilic liquids include liquidswhich are obtained from natural sources, exemplified by essential oilsas well as oils which can be synthesized, for example, vitamin A.

Essential oils are lipophilic liquids obtained from natural sources.They may be obtained by physical process such as, for example, pressingplant material or by extraction or distillation processes. In general,they are a mixture comprising one or more volatile oils and may alsoinclude other materials which are soluble in the volatile oil(s).Essential oils may comprise, as well, one or more constituents that havepartial miscibility with water. Examples of essential oils include thosewhich have organoleptic properties, for example, odor or tasteproperties as possessed, for example, by eucalyptus oil and those thathave as well pharmaceutical properties, for example, as possessed bypine needle oil which has expectorant properties.

Waters, essences, and extracts exemplify essential oils which have somewater miscibility, and in general comprise the essential oil, water, anda component which improves their solubility in water, for example, aglycol or an alcohol. They are obtained from plant materials using steamextraction/distillation (waters), alcohol extraction (essences), andextraction by a water/alcohol mixture (extracts). An example of a wateris peppermint water. Examples of essences and extracts are valerian oil,eucalyptus oil, and fennel oil.

Other examples of essential oils include allspice, amber, americanwormseed, angelica, anise, anise japanese, anthemis, arbor vitae,asarum, balm, basil, bay, bergamot, bitter almond, bitter orange, cade,cajeput, calamus, canphora, canada fleabane, canada snakeroot, caraway,cannabis, cardamon, cascarilla, cashew nut shell, cassia, castor, cedarleaf, cedar wood, celery, champaca, chenopodium, cherry laurel, chinesecinnamon, cinnamon, cinnamon ceylon, citronella, clove, copaiva,coriander, crisp mint, cubeb, cumin, curlet mint, cypress, dill, dwarfpine needles, egg yolk, erigeron, fennel, fir, fleabane, garlic,geranium, ginger, grapes, green oil, hedeoma, hops, hyssop, jojoba,juniper, lavender, lecithin, lemon, levant worm seed, linaloe, mace,majoran, melissa balm, mirbane, monarda, mountain pine, mustardexpressed, myrcia, miristica, mirtle, meroli, niaoli, niove, nut,nutmeg, orange, orange flowers, origanum, palma christy, parsley,patchuli, pelargonium geranium, pennyroyal, pepper, peppermint,pettigrain, pimento, pine, pulegium, rice brain, rose, rose geranium,rosemary, rue, santal, sassafras, savin, scotch fir, silver fir, silverpine, spearmint, spike, sweet almonds, sweet bay, sweet flag, tansy,thuya, thyme, turpentine, valerian, vetiver, white cedar, wild marjoran,wine, wine heavy, worm wood, yarrow, sweet orange, white birch. Amixture of two or more lipophilic liquids can be used in formulating thecomposition of the present invention.

The hydrophilic dispersant for use in the practice of the presentdevelopment is a solid at room temperature (about 25° C.). Thedispersant also has a water solubility at room temperature such that atminimum it meets the USP 24 definition of “freely soluble”, that is, itrequires no more than 10 weight parts of water to completely dissolve 1weight part of dispersant, and the dispersant is sufficiently lipophilicto permit it to be “wetted” by the lipophilic liquid; however, itslipophilic properties are such that it is not soluble to any appreciabledegree in the lipophilic liquid, that is, its solubility in thelipophilic liquid is no greater than about 0.1 wt. % at roomtemperature. It is believed that the lipophilic properties of thedispersant are associated with its functioning as a thickening agent forthe lipophilic liquid. As example of the degree to which the lipophilicliquid and solid hydrophilic dispersant interact is that a mixture ofthe lipophilic liquid and the dispersant can have the characteristics ofa flour dough of the type used in baked goods.

Without wanting to be bound by theory, it is believed that the solidhydrophilic dispersant functions in various ways in the formation of thecomposition of the present invention and its properties. It is believedthat the dispersant helps the lipophilic liquid to “wet” the surface ofthe particulating agent (described below) during the formation of thesolid particulates of the present invention. The ability of thedispersant to promote such “wetting” is believed to be important inpromoting the homogeneous dispersion of the liquid constituent in theindividual particulates comprising the composition. Additionally, it isbelieved that the dispersant functions to produce particulates that havea dry appearance and acceptable flowability (described below). This isin contrast to particulates that have poor flowability and an oilyappearance. It is believed also that the dispersant plays a role in theability of the lipophilic liquid to be retained in the composition, forexample, when a powdery form thereof is subjected to pressure and shapedinto a tablet. This is in contrast to particulates that exude oil whensubjected to pressure.

The hydrophilic solid dispersant is believed also to aid in dispersingthe lipophilic liquid from the solid form of the composition when it iscontacted with an aqueous medium. As mentioned above, it is believedthat the present invention will be used widely to form powders fromwhich there are formed bioactive tablets for oral ingestion. In use, thetablets come into contact with aqueous-based body fluids. It is believedthat the dispersant aids in dispersing the lipophilic liquid throughoutthe aqueous media when the tablet is contacted therewith. This isbelieved to be accomplished by virtue of the dispersant's interactingwith the particulating agent whose surface has hydrophilic properties.It is thought that the surface of the particulating agent is wetted withthe aqueous medium and that this aids in releasing the lipophilic liquidfrom the particulating agent.

Considering the above discussion of how the dispersing agent is believedto function, it should be appreciated that, in selecting a particulardispersing agent for use in the practice of the present invention, thereshould be taken into account the balance between lipophilic andhydrophilic portions of the agent as well as the character of theparticular lipophilic liquid and of the particular particulating agentused.

Examples of solid hydrophilic dispersing agents suitable for use as aconstituent in the practice of the present development are: (1)polyhydroxyalcohols, for example, sorbitol, mannitol, xylitol, andmaltitol; (2) sugars, for example, fructose, glucose, and mannose; and(3) polysaccharides, for example, saccharose, galactose, maltose,cellobiose, cellulose, starches, dextrin, chitin, cyclodextrin, andjaluronic acid. A mixture of two or more dispersing agents can be usedin formulating the composition of the present invention.

In preferred form, the hydrophilic dispersing agent is selected so thatit improves the cohesive properties of a tablet that is formed from apowdery form of the composition. Cohesion can be evaluated from ameasurement of tablet hardness and friability (discussed below). Anexample of a hydrophilic solid dispersing agent which promotes cohesionis mannitol. If the hydrophilic dispersant does not promote cohesion,cohesion enhancers, for example, starch, can be added to formulationsintended for use in forming tablets. This typically adds to the size ofthe tablet. Thus, a dispersant which also promotes cohesion isadvantageous in reducing tablet size. This is a particular advantagewhen making tablets from particulates incorporating oils of lowactivity. The use of such oils requires that a relatively large amountof particulate be incorporated into the tablet, thus increasing size.

Particulating agents suitable for use in the practice of the presentinvention may have various properties. One is a surface that can bewetted by both water and a solution of the hydrophilic solid dispersant.It can be characterized further in that, when placed in contact with anequal volume of neutral water, the pH of the water remains between aboutpH3 and about pH9. The particulating agent can be further characterizedin that, upon contact with water, the surface of the agent undergoes ahydrolysis reaction. Additionally, a particulating agent for use in thepractice of the present invention is compatible, i.e. does not react,with the lipophilic liquid constituent(s) of the composition.

Preferably, the particulating agent has a relatively high mass specificsurface area, typically greater than about 25 m²/g. For applications inwhich the composition comprises an ingestible material, theparticulating agent is preferably a material generally recognized assafe (GRAS) for ingestion.

Examples of particulating agents suitable for inclusion in particulatesof the present development are silicon dioxide particulates, forexample, silica gels and aerosils, titanium oxide particulates, forexample titanium oxide-based gels and aerogels, and magnesiumtrisilicate. An example of a suitable aerosil is Degussa Aerosil 200®(Degussa).

The composition of the present invention can include other constituentswhich impart desired properties to the composition. Examples of suchmaterials are flavoring agents, lubricants, sweetening agents, binders,fillers, taste masking-agents, and other excipients known in the art.

The composition of the present development is made by mixing thelipophilic liquid, the hydrophilic dispersing agent, and theparticulating agent. In preferred form, the composition of the presentinvention can be prepared by admixing the particulating agent with amixture comprising the lipophilic liquid and the hydrophilic liquiddispersant. The mixture of lipophilic liquid and dispersant can beprepared in any suitable way. For example, the dispersant can be addedto the lipophilic liquid held, for example, in a mixing container or thelipophilic liquid can be added to the dispersant which is held in suchcontainer. The lipophilic liquid and dispersant are mixed for asufficient period of time to produce a homogeneous composition, forexample, a composition which is in the form of a batter-like,paste-like, or dough-like material comprising the constituents.Thereafter, the particulating agent is added to the lipophilicliquid/dispersant mixture (precursor composition) or the mixture isadded to the particulating agent and the resulting composition is mixeduntil particulates comprising the aforementioned materials are obtained.

The preparation of particulate and precursor compositions can beeffected at room temperature or ambient conditions and in conventionalblending or mixing equipment. The particulate and precursor compositionscan be prepared in equipment of any suitable scale, for example, inmanual mixing equipment which relies on the use of a paddle or a spatulaor in motorized equipment, for example, an electric mixer or blender.Inasmuch as the particulates can be prepared at room temperature, it isfeasible to formulate the particulates from materials which are volatileor heat-sensitive.

The following guidelines are set forth for selecting the proportion ofthe ingredients that comprise the composition of the present invention.The lipophilic liquid should be present in an amount at least sufficientto impart to the composition those properties which are contributed bythe lipophilic liquid to the composition. For use in bioactivecompositions, the amount of the bioactive lipophilic liquid should be anamount at least sufficient for a dosage form thereof to exhibit thedesired bioactive effect. The hydrophilic liquid dispersant should beused in an amount at least sufficient to convert the lipophilic liquidinto a pourable thickened mass and the particulating agent should bepresent in an amount at least sufficient to convert the aforementionedthickened mass into a dry particulate mass having the liquid componenthomogeneously distributed therein.

In determining the maximum amount of each of the constituents comprisingthe composition, the following considerations should be taken intoaccount. With respect to the lipophilic liquid, excessive amounts of theliquid will yield a material which exudes oil under pressure. Evengreater excesses of the liquid will result in a particulate that isoily. With respect to the hydrophilic solid dispersant, an amount whichprovides a paste-like consistency should be used, with the maximumamount providing a mass which has shape-retaining properties, about theconsistency of wet clay. An excessive amount of the dispersant, whenmixed with the liquid component, will result in a mass which does notflow under pressure. With respect to the particulating agent, themaximum amount of agent usable is that amount that gives minimum averageloading of the liquid component to the product particulate withoutresulting in a non-homogeneous distribution of the liquid componentsacross the particulate mass.

It is believed that for most applications, the preferred compositionwill comprise about 25 wt. % to about 55 wt. % of the lipophilic liquid,about 25 wt. % to about 45 wt. % of the hydrophilic solid dispersant,and about 15 to about 30 wt. % of the particulating agent. For use inpreparing particulates of the present invention that can be used informulating tablets, a preferred formulation comprises the compositionin which the weight ratio of hydrophilic dispersant to lipophilic liquidis between about 0.5 to 1 and about 1.5 to 1 and the weight ratio oflipophilic liquid to particulating agent is between 1 to 1 and about 3to 1.

Generally speaking, the process of the present invention may yieldparticulates having a wide variation in average particle size, typicallyfrom about 5 microns to about 300 microns. It should be appreciated thatsuch particulates will include particles having sizes outside of theaforementioned range, that is, some particles that are less than about 5microns and some greater than about 300 microns. The particulates of thepresent invention can be separated into collections of particles havingaverage particle sizes outside of the afore mentioned ranges, forexample, by sieving or other means known in the art. In the case whereit is desired to have a collection of particulates of relatively largeraverage particle size, the particulates of the present invention can besubjected to an agglomeration process, for example granulation, toproduce particulates having an average particle size greater than 300microns, while retaining the essential features described above. Thus,particulates can be agglomerated to form beads or pellets.

Powders for use in forming tablets in accordance with the presentinvention will typically have an average particle size of about 50microns to about 200 microns, and may be obtained by the processdescribed above, for example, by sieving the particulates to select thefraction having the desired average particle size.

The particulates of the present development, and thereby the liquidconstituents contained there, can be formulated into compositions of anyform suitable to the purpose, for example, powders suitable for pressinginto tablets and granulates suitable for use in producing beverages.Examples of such compositions are given below. Exemplary tabletscomprise fast-melt, chewable, and ingestible formulations. A formulationcomprising a granulated “dry syrup” is also given below as an example ofa formulation comprising a particulate of the present development fromwhich a beverage can be prepared. The term “dry syrup” is used to denotea composition in powdery form that is dissolved in water to produce apotable liquid that includes components having desirable organolepticactivity.

EXAMPLES

There are presented below examples of the preparation of compositions inaccordance with the present development, including powdery formsthereof, and examples of comparative compositions. The examples includean evaluation of the following properties of particulates which are thesubject of the examples: flowability; homogeneity; and density.

Flowability was evaluated by measurement of the angle of repose using adynamic method. In flowability determinations, about 30 g of sample ofparticulate was dispensed from a 0.6 cm diameter tube having afunnel-shaped top with the bottom positioned 2 cm above a flat receiver.The angle of repose was calculated from the diameter of the circlecovered by the dispensed sample. The procedure was carried out asdetailed in Lieberman, H. A. and Lachman, L, “Pharmaceutical DosageForms: Tablets” Vol. 2, Marcel Dekker, NY, (1981) pp 26-29. It ispreferred that particulates that are powders for use in preparingtablets exhibit an angle of repose, as determined by these measurements,of between about 28 degrees and about 45 degrees.

The homogeneity of the particulates was evaluated for appearance (visualhomogeneity) and for consistency of the amount of bioactive materialcontained in randomly drawn aliquots (doses) of the particulates (dosagehomogeneity).

Visual homogeneity was evaluated for those particulates in which thelipophilic liquid imparts a distinctive coloration to the particulates.A sample of particulate was considered to have visual homogeneity, when,viewed on a grain to grain comparison, the particulates had a uniformcolor (no significant lighter or darker grains). In samples where somegrains of the particulate were markedly darker or lighter than theaverage tone of the sample, the particulate was considered to bevisually non-homogeneous. Particulates of the examples were alsoevaluated visually to determine if they had an oily appearance. None ofthe exemplary particulates of the present development had any visualtrace of oil on their surfaces.

Dosage homogeneity was determined by extracting the bioactive materialfrom random samples of particulate into a solvent and quantifying theamount of bioactive material extracted via high pressure liquidchromatographic measurement using art recognized methodology. This wasperformed according to Uniformity of Dosage Unit, Monograph 905,beginning of page 2001 as described in the US Pharmacopoeia 24 (USP 24).The particulate was considered to have dosage homogeneity if 9 out of 10randomly selected dosage units assay in the range of 85% to 115% of thecalculated bioactive material content, or 10 out of 10 randomly selecteddosage units assay in the range of 75% to 125% of the calculatedbioactive material content of the average dose, for a set ofmeasurements where the individual values display a correlationcoefficient that indicates no greater than 6% variability betweenindividual measurements. A composition comprising particulate materialof the present invention is considered to have a liquid componentdispersed uniformly throughout the composition if it demonstratesaccording to the above described test that it has dosage homogeneity.

In addition, the density of exemplary particulates was evaluated byobtaining bulk and tapped density measurement on a sample of particulateaccording to the procedure described in section 2.9.15 of the EuropeanPharmacopoeia, 2001 edition (EP), and calculating from thosemeasurements the Carr index of the particulate according to theprocedure described in “Granulation, Tabletting, and CapsuleTechnology”, pp 18-21, June 2001, The Hague Center for ProfessionalAdvancement. Bulk and tapped density measurements were carried out on anErweka tapped volumeter apparatus in accordance with the EP and USP 24listed procedures. A Carr index of less than 15% was consideredindicative of a preferred particulate for use in tablet formulations.

Various of the examples below also describe the preparation of tabletsfrom a powdery form of particulates of the present development. Thetaste and following physical properties of the tablets were alsoevaluated: hardness; friability; homogeneity; and dispersibility in thecase of fast-melt and ingestible composition.

Hardness was evaluated on a Schloninger tablet hardness testingapparatus according to the procedure described in Remington'sPharmaceutical Sciences (17^(th) Edition), Mack Publishing Co., 1985,pp. 1608-1609. For fast-melting composition tablets, a hardness rangingfrom about 1 to about 10 kiloponds (Kp) was considered acceptable. Forchewable tablets, a hardness range of about 1 to about 25 Kp wasconsidered acceptable. And for ingestible tablets, a hardness range ofabout 10 Kp to about 20 Kp was considered acceptable.

Friability was determined using a Sotax F2 instrument according to theprocedure described in the USP Pharmacopoeia, monograph 1216, beginningpg, 2148. The European Pharmacopoeia, 3^(rd) edition, lists acceptablevalues of friability for uncoated tablets as less than one wt. %.

Both visual and dosage homogeneity of the tablets were evaluated. Visualhomogeneity was evaluated by inspecting samples of the tablets. Tabletsthat were free of spots remarkably darker than the average color of thetablet or free of a “stained” appearance were classified as beingvisually homogeneous. The presence of the aforementioned types of spotsand staining are caused by the lipophilic liquid exuding into thevarious tablet excipients surrounding a grain of the powder. Dosagehomogeneity of tablets were evaluated by determining the variability (ifany) in the amount of bioactive material contained in the tabletaccording to the same procedure described above for determining dosagehomogeneity in the particulates.

The dispersibility of fast-melting and ingestible tablets was evaluatedusing a Sotax DTX3 Disintegration tester according to the proceduredescribed in Remington's Pharmaceutical Sciences (17^(th) Edition), MackPublishing Company, 1985, pp. 1609-1610. Acceptable dispersion times forfast-melt tablets are generally less than about 15 minutes afterimmersion of the sample in the dispersing solvent. For ingestibletablets, acceptable dispersion times are generally less than about 30minutes after immersion in the dispersing solvent.

Organoleptic properties (taste sensations) of the tablets were evaluatedsubjectively by a panel of testers. Samples of the tablets wereadministered to volunteers who rated them on an arbitrary scale of 1 to5 for flavor and lack of objectionable taste sensations such asbitterness or anesthetic taste. The ratings in each category wereaveraged for all the testers. A formulation was determined to haveacceptable taste when the average rating indicated that it had low or noobjectionable taste sensations associated with it and, in addition,possessed a discernable degree of desirable taste sensations.

The first two groups of examples illustrate the preparation according tothe present development of free-flowing particulates that comprise alipophilic liquid.

The first group of seven examples is illustrative of compositionsprepared by placing the lipophilic liquid into an open bowl, addingthereto a hydrophilic solid dispersant, and mixing the ingredientsmanually by means of a spatula until a homogeneous mixture of theingredients was obtained. The mixture had the form of a paste. Aparticulating agent was added then to the mixture and manual blendingwas continued until a dry, free-flowing particulate was obtained.Blending was carried out under ambient conditions, typically, atemperature of less than about 30° C. and about 35% relative humidity.

The lipophilic liquid of the compositions of the first group of exampleswere oils derived from natural sources; they were all obtained fromeither Pharmabase or Geobell, AG, and used as received. Theparticulating agent was Aerosil A 200® silica from Degussa. Thehydrophilic solid dispersants used in the compositions of the firstgroup of examples are identified below in Table 1. They were obtainedfrom Roquette.

The constituents (and amounts) comprising the compositions of the firstgroup of examples are identified below in Table 1. TABLE 1 Ex.Lipophilic Liquid, Hydrophilic Solid Particulating No. 50 g Dispersant,50 g Agent, wt. 1 lycopene oil Mannitol silica, 25 g 2 orange oilmaltodextrin silica, 20 g 3 fennel oil Mannitol silica, 20 g 4 lecithinoil Sorbitol silica, 30 g 5 clove oil Sorbitol silica, 25 g 6 eucalyptusoil Sorbitol silica, 25 g 7 Pine needle oil maltodextrin silica, 25 g

The particulates comprising the constituents of Table 1 above wereevaluated according to the procedures described above and determined tobe non-oily, homogeneous, and free-flowing. They were further determinedto have a Carr index of less than 15% which is a range suitable forpreparing tablets from the particulates.

The second group of examples describes compositions which were preparedby first placing the hydrophilic solid dispersant into an open bowl andadding gradually a lipophilic liquid with blending until all of theliquid had been added and a homogeneous mixture had been obtained. Aswith the first group of examples, the mixture was in the form of paste.Thereafter, a particulating agent was added. As with the first sevenexamples, blending was carried out manually, using a spatula, underambient conditions. The oils used in preparing the second group ofexamples were derived from natural sources and obtained as items ofcommerce from Geobell, AG. The oils were used as received. Mannitol wasemployed as the dispersant and silica was employed as the particulatingagent; they were obtained from the same sources and the powders wereprepared in the same manner as described above.

The constituents (and amounts) comprising the compositions of the secondgroup of examples are identified below in Table 2. TABLE 2 Ex.Lipophilic Liquid, Hydrophilic Solid Particulating No. 50 g Dispersant,50 g Agent, Wt.  8 vitamin A oil Mannitol Silica, 25 g  9 juniper oilMannitol Silica, 25 g 10 valerian oil Mannitol Silica, 20 g

The compositions of Table 2 were also evaluated by the proceduresdescribed above. They were determined to be non-oily, free-flowing,homogeneous particulates. Based on density measurements as describedabove, they were also determined to be good candidates for incorporationinto tablet formulations.

Taken together, the first and second groups of examples demonstrate thatthe lipophilic liquid and the hydrophilic solid dispersing agent can beadded in any order in preparing a homogeneous mixture of the two, priorto blending with a particulating agent to form a composition of thepresent development.

The next example is comparative in nature.

Example No. C-1

For comparative purposes, there was prepared a composition consisting ofonly a lipophilic liquid and a particulating agent. It was prepared inthe manner described above for the previous examples. Thus 50 g oflycopene oil and 25 g of silica were blended in a bowl using a spatula.The resulting material produced a visually non-homogeneous, clumpy(non-free flowing) particulate solid. Addition of a hydrophilic soliddispersant (mannitol, 50 g) to this material did not improve theappearance or pour characteristics of the composition.

The next three groups of examples are illustrative of the formation oftablets containing powdery fractions of particulates (hereinafter,“powders”) selected from those prepared in Example Nos. 1 to 10 and C-1above. The first group of these examples illustrates the use of thepowders prepared according to the present development in fast-meltingtablets (intended to be dissolved in the buccal cavity) and, forcomparison, a fast-melting tablet prepared from the powder of ExampleNo. C-1 (lycopene oil absorbed on silica alone). The second groupexemplifies the use of the powders in forming chewable tablets and thethird group exemplifies the use of the powders in tablets intended fororal ingestion and delivery of bioactive ingredients to thegastrointestinal tract (hereinafter “ingestible tablets”).

The examples in this group (Example Nos. 11 to 14) show theincorporation into rapidly dissolving tablet formulations of lycopenepowder, juniper powder, and clove powder produced by the method of thepresent development and, for comparison, powder produced by theabsorption of lycopene oil onto silica alone. Lycopene is administeredcommonly as an antioxidant. Juniper oil is administered as a diureticagent and clove oil is administered as an analgesic. The examplesdemonstrate that these liquids can be incorporated into rapidlydissolving tablets after converting them to powders using the method ofthe present development. The tablets of these examples undergo rapiddissolution when placed into the buccal cavity. Rapid dissolutionproperties are imparted to the tablets by including in their formulationa composition (hereinafter “base powder”) produced by granulatingmannitol, sorbitol, and citric acid in an Aeromatic Strea 1 fluid bedgranulator using a water/polyethylene glycol (PEG 6000) granulatingsolution.

To prepare the base powder, measured amounts of mannitol, sorbitol, andcitric acid were placed together into the cone of the fluid bedgranulator and fluidized with air at a temperature of about 40° C. About30 ml of a granulating solvent comprising demineralized water and PEG6000 were passed into the granulator at a rate of about 10 ml/minute.After all of the granulating solvent had been introduced into thegranulator, the resulting granulated material was dried by continuingthe flow of dry air for about 20 minutes at about 50° C.

To prepare a composition for tableting, the base powder and the otherdry constituents were placed into an Erweka cube blender and blended for15 minutes. At the end of 15 minutes, an admixture of the constituentsin the form of a homogeneous powder was obtained. Aliquots of thispowder were then tableted in a Ronchi CT 20 eccentric tableting pressfitted with a toroidal punch of 13 mm in diameter. The stroke of thepress was adjusted to provide sufficient pressure to produce tabletsdisplaying little friability under ordinary handling conditions.

Example No. 11 Tablets Containing Lycopene Powder

A fast-melting tablet base powder was prepared by granulating 30.38 g ofmannitol, 19.71 g of sorbitol, and 2.16 g of citric acid together with awater solution containing 20 g of demineralized water and 1.08 g of PEG6000 using the granulating procedure described above. The powder fromwhich the tablets were formed was prepared in a blender by blending: (A)53.33 g (dry weight) of the aforementioned fast-melting tablet basepowder; (B) 41.67 g of lycopene powder prepared according to Example No.1; and (C) 1.00 g of magnesium stearate, 2.00 g of wild berry flavor(Sensient) and 2.00 g of aspartame (HSC). The resulting homogeneouspowder was removed from the blender and compressed into tablets weighing500 mg using the equipment and procedure described above. Each tabletcontained 15.00 mg of the lycopene oil used in the preparation of thelycopene powder.

The physical and organoleptic characteristics of the tablets wereevaluated according to the procedures described above. The tablets hadacceptable dissolution and taste characteristics. Additionally, theywere found to have hardness and friability characteristics sufficient toendure the rigors of ordinary handling.

Example No. 12 Tablets Containing Juniper Powder

A fast-melting tablet base powder was prepared by granulating 40.10 g ofmannitol, 26.02 g of sorbitol, and 2.85 g of citric acid together with awater solution containing 50 g of demineralized water and 1.43 g of PEG6000 using the granulating procedure described above. The powder fromwhich tablets were formed was prepared in a blender by blending: (A)70.40 g (dry weight) of the aforementioned base powder; (B) 25.00 g ofjuniper powder prepared according to Example 9; and (C) 1.00 g ofmagnesium stearate, 1.60 g of fresh mint flavor (Givaudan) and 2.00 g ofaspartame (HSC). The homogeneous powder was removed from the blender andcompressed into tablets weighing 500 mg using the equipment andprocedure described above. Each tablet contained 50.00 mg of juniper oilused in the preparation of the juniper powder of Example No. 9.

The physical and organoleptic characteristics of the tablets wereevaluated according to the procedures described above. The tablets hadacceptable dissolution and taste characteristics. Additionally, theywere found to have hardness and friability characteristics sufficient toendure the rigors of ordinary handling.

Example No. 13 Tablets Containing Clove Powder

A fast-melting tablet base powder was prepared according to theprocedure described for Example No. 11 above. A powder suitable forforming tablets was prepared in a blender by blending: (A) 70.40 g (dryweight) of the base powder; (B) 20.00 g of clove powder preparedaccording to Example No. 5; and (C) 1.00 g of magnesium stearate, 1.60 gof cinnamon flavor (Sensient), and 2.00 g of aspartame (HSC). Theresulting homogeneous powder was removed from the blender and compressedinto tablets weighing 500 mg using the equipment and procedure describedabove. Each tablet contained 40.00 mg of the clove oil used in thepreparation of the clove powder.

The physical and organoleptic characteristics of the tablets wereevaluated according to the procedures described above. The tablets hadacceptable dissolution and taste characteristics. Additionally, theywere found to have hardness and friability characteristics sufficient toendure the rigors of ordinary handling.

The next example is comparative in nature.

Example No. C-2

For comparison purposes, a fast-melting tablet (without a hydrophilicsolid dispersant) was prepared by blending: (A) 53.33 g (dry weight) ofthe fast-melting tablet base powder prepared according to Example No.11; (B) 41.67 g of lycopene oil absorbed onto silica, prepared accordingto Example No. C-1; and (C) 1.0 g of magnesium stearate, 2.0 g of wildberry flavor (Sensient) and 2.0 g of aspartame (HSC). Tablets wereproduced from this admixture using the same procedure and conditionsused to prepare the tablets of Example No. 11.

The physical properties of these tablets were compared with those of thetablets of Example No. 11. Tablets of the present example fractured at alower force than those of Example No. 11, the tablets of the presentexample fracturing at 1 Kp or less. They also displayed extremefriability in that the tablets of the present example shattered to theextent that their friability was not measurable. Visual comparisonbetween the tablets of Example No. 11 and Example C-2 showed thatlycopene oil exuded from the silica in the tablets of the presentexample, whereas no exudation was observed in the Example No. 11tablets. Exuded lycopene oil in the tablets of the present example wasparticularly noticeable in those areas of the tablets that weresubjected to the highest pressures during tableting, that is, at thejunction between the rounded edge and the center web of thetoroidal-shaped tablet, where streaks of lycopene oil were observed.Throughout all areas of tablets of the present example, spots oflycopene oil stained the tablets.

The next group of examples illustrates the formulation of chewabletablets containing eucalyptus powder and pine needle powderrespectively. Eucalyptus and pine needle oils are typically used asflavoring and expectorants in pharmaceutical preparations. The examplesdemonstrate that such oils can be incorporated into a chewable tablet byfirst incorporating them into a particulate using the method of thepresent development.

Example No. 15 Tablets Containing Eucalyptus Powder

Using the blending procedure described above for Examples Nos. 11 to 14,a homogeneous powder containing: (A) 5.95 g of eucalyptus powderprepared according to Example No. 6; (B) 57.31 g of low-fat milk powder(Sanolait® COOP); (C) 36.18 g of fructose (Centonze); (D) 0.24 g offresh mint flavor (Givaudan); and (E) 0.32 g of magnesium stearate wasprepared. The homogeneous powder thus prepared was tableted bycompressing an aliquot of the powder in a Ronchi CT 20 eccentrictableting press fitted with a plane punch of 18 mm diameter andsufficient pressure to obtain a cohesive tablet. The tablets weighed2100 mg. Each contained 50.0 mg of the eucalyptus oil used inpreparation of the eucalyptus powder.

The physical and organoleptic characteristics of the tablets wereevaluated according to the procedure described above. The tablets werefound to have acceptable dissolution characteristics as defined forchewable tablets above. Additionally, they were found to have acceptabletaste characteristics when chewed and sufficient hardness and resistanceto friability to endure the rigors of ordinary handling, as thosequalities were defined above for chewable tablets.

Example No. 16 Tablets Containing Pine Needle Powder

Using the blending procedure described above for Example No. 15, ahomogeneous powder containing: (A) 5.95 g of pine needle powder preparedaccording to Example No. 7; (B) 52.60 g of low fat milk powder(Sanolait® COOP); (C) 40.90 g of glucose (Centonze); (D) 0.23 g of freshmint® flavor (Givaudan); and (E) 0.32 g of magnesium stearate wasprepared. This homogeneous powder was tableted using the proceduredescribed in Example No. 15, yielding 2100 mg tablets. Each tabletcontained 50.0 mg of the pine needle oil used in preparation of the pineneedle powder.

The physical and organoleptic characteristics of the tablets wereevaluated according to the procedure described above. The tablets werefound to have acceptable dissolution characteristics. Additionally, theywere found to have acceptable taste characteristics when chewed andsufficient hardness and resistance to friability to endure the rigors ofordinary handling.

The next group of examples illustrates the incorporation of lecithinpowder, vitamin A powder, and fennel powder prepared according to themethod of the present development into ingestible tablets. Vitamin A oilis a dietary supplement. Lecithin and fennel oil can be used asdiuretics or dietetic supplements. The examples demonstrate that theseoils can be incorporated into ingestible tablets by first convertingthem into a particulate using the method of the present development.

In these examples (Nos. 17 to 19), a precursor of the granulated basecomposition of the tablet (granulate precursor) is prepared by drying at85° C. to 1% relative humidity a solution comprising 20 g of Mays starch(Centonze), 80 g of demineralized water, and in amounts identifiedbelow, lactose and poly(vinyl pyrrolidone). The resulting solid is thengranulated in a Aeromatic Strea 1 fluid bed granulator. The granulatedmaterial is sieved to isolate granulate which has a nominally 1.5 mmaverage diameter and which serves as the tablet base (hereinafter“granulated base composition”).

The granulated base composition was converted to a powder from whichtablets were made by blending it and other dry constituents, asdescribed below, in an Erweka cube blender for 15 minutes. At the end of15 minutes, a homogeneous powder was obtained. Aliquots of the powderwere tableted using a Ronchi CT 20 eccentric tableting press fitted witha scored 8 mm diameter punch using sufficient pressure to producetablets displaying little friability under ordinary handling conditions.The hardness, friability, and dissolution characteristics of the tabletsof this group of examples were evaluated using the equipment andprocedures described above.

Example No. 17 Tablets Containing Lecithin Powder

An ingestible tablet was prepared by adding to the granulate precursordescribed above 70.07 g of lactose (Selectchemie) and 2.5 g ofpoly(vinyl pyrrolidone), which was then dried and granulated asdescribed above. Into a Erweka cube blender were placed 172.57 g of thedried granulate prepared for this example. To this were added 6.50 g oflecithin powder prepared according to Example No. 4 and 0.93 g ofmagnesium stearate. The constituents were blended according to theprocedure described above to obtain a homogeneous dry powder.

The resulting powder was tableted as described above into tabletsweighing 200 mg. Each tablet contained 5.00 mg of the lecithin oil usedin preparing the lecithin powder.

The resulting tablets were evaluated as described above. The resultsshowed that the tablets had dissolution properties within an acceptablerange and showed sufficient hardness and resistance to friability towithstand the rigors of ordinary handling. Additionally, visualinspection of the tablets showed that they had a regular surface andwere without edge erosion.

Example No. 18 Tablets Containing Vitamin A Powder

A granulated base composition was prepared by adding to the granulateprecursor described above for this group of examples 75.17 g of lactoseand 2.5 g of poly(vinyl pyrrolidone). The resulting mixture was thendried and granulated as described above in Example No. 17.

Into an Erweka cube blender were placed 177.67 g of the granulated basecomposition, 1.40 g of vitamin A powder prepared according to ExampleNo. 8, and 0.93 g of magnesium stearate. The dry materials were blendedaccording to the procedure described above to produce a homogeneouspowder admixture. The powder was tableted as described above intotablets weighing 200 mg. Each tablet contained 0.800 mg of the vitamin Aused in preparing the vitamin A powder.

The resulting tablets were evaluated as described above and showedphysical characteristics within acceptable ranges. The tablets werevisually evaluated and found to have a regular surface and be devoid ofedge erosion.

Example No. 19 Tablets Containing Fennel Powder

An ingestible tablet base composition was prepared by adding to thegranulate precursor described above for this group of examples 74.17 gof lactose and 2.5 g of poly(vinyl pyrrolidone). The resulting mixturewas then dried and granulated as described in Example No. 17.

Into an Erweka cube blender were placed 100 g of the granulated basecomposition prepared for this example, 2.40 g of fennel powder preparedaccording to Example No. 3, and 0.93 g of magnesium stearate. Theconstituents were blended according to the procedure described above toyield a homogeneous powder admixture. The resultant powder was tabletedas described above into tablets weighing 200 mg. Each tablet contained2.00 mg of fennel oil used in preparing the fennel powder.

The resulting tablets were evaluated as described above and showedphysical characteristics within acceptable ranges. The tablets wereevaluated visually and found to have a regular surface and be devoid ofedge erosion.

Example No. 21 Dispersible Granulate Containing Valerian Particulate

This example illustrates the use of a valerian oil particulate of thepresent development as a constituent in a granulate formulation (“drysyrup”) which is dispersed into a hot liquid prior to consumption by theuser. Valerian oil is exemplary of oils used in sedative formulations.This example demonstrates that such oils may be incorporated intoparticulates from which they may be dispersed readily if the oil isfirst incorporated into a solid form using the method of the presentdevelopment.

A granulating solvent was prepared by combining about 30 g ofdemineralized water with about 1.00 g of Tween® 80 (a polyglycolizedether having surface active properties, Fluka). A granular basecomposition was prepared by placing 88.57 g of sucrose (Zucker MuhleRupperswill), 1.00 g of aspartame (HSC), 2.80 g of citric acid (Roche),4.00 mg of Brilliant Blue (E133 Flachsmann), 8.00 mg of riboflavin5-phosphate dehydrate (CFS), and 1.20 g of Mays starch (Centonze) intoan Aeromatic Strea-1 fluid bed granulator. The dry constituents werefluidized using air at about 40° C. and granulated by introducing about10 ml of the granulating solvent to the granulator over a period ofabout 2 minutes while maintaining a 40° C. temperature. After all of thegranulation solvent had been introduced, the granulated material wasdried by continuing the flow of fluidizing air for about 30 minutes at50° C.

Into an Erweka cube blender were placed 100 g of the dry granular basecomposition prepared for this example. To the dry granular base wereadded 5.00 g of valerian oil granulate prepared according to Example No.10, 0.32 g of mint flavor (Givaudan), and 0.10 g of Aerosil A200®(Degussa). The resulting mixture was blended for 15 minutes to obtain ahomogeneous admixture. Aliquots of the admixture weighing 2.50 g werepackaged into sachets. Each package contained 50.00 mg of the valerianoil used in preparing the valerian particulate.

The dissolution characteristics of the sachets were evaluated by placingthem in demineralized water at ambient temperature (about 20° C.) andobserving that the admixture dispersed completely within 60 seconds. Theresulting liquid dispersion was evaluated for taste using the proceduredescribed above. The results indicated that the sachets produced anacceptable tasting beverage.

The next example compares the loss due to vaporization from a sample ofliquid eucalyptus oil and from a particulate incorporating eucalyptusoil according to the present development. Eucalyptus oil is a volatileoil used as a flavoring agent.

Example No. 22 Comparison of Vapor Losses From Liquid

A powder containing eucalyptus oil was prepared according to theprocedure described above by placing 2 grams of eucalyptus oil into abowl and mixing into it, using a spatula, 2 grams of sorbitol. When themixture had formed a homogeneous mass, 1 gram of silica (Aerosil 200®,Degussa) was blended in, with continued mixing, until a free-flowingparticulate had been formed. The particulate was placed into an openvessel having a volume of 50 ml and an opening of about 12 cm². Into anidentical vessel were placed 2 grams of eucalyptus oil of the same typeused to prepare the powder. The vessels were stored under identicalconditions and weighed periodically to determine the amount of oil thatwas lost due to vaporization from the vessels. The results are presentedin FIG. 1 as a percent loss of the initial amount of oil present in thevessels. FIG. 1 demonstrates that, although the oil incorporated intothe particulate is spread out over a much larger surface area than inthe liquid sample (the surface area of the silica used in preparing theparticulate was 200 m²), the loss therefrom due to volatility is aboutthe same as would be observed from the liquid.

1. A method for forming a composition in solid particulate form from amixture of constituents, at least one of which is a liquid, comprisingforming said composition from a mixture of constituents comprising alipophilic liquid, a hydrophilic solid dispersant, and a solidparticulating agent.
 2. The method of claim 1 wherein said compositionis formed by adding said particulating agent to a mixture of said liquidand solid dispersant.
 3. A method of claim 1 or 2 wherein said liquidincludes a bioactive material.
 4. The method of claim 1, 2 or 3 whereinsaid agent is silicon dioxide.
 5. A method of any one of claims 1 to 4,wherein the lipophilic liquid is lycopene, the hydrophilic soliddispersant is mannitol, and the particulating agent is silica.
 6. Amethod of claim 5, wherein the lipophilic liquid and solid dispersantare combined in a weight ratio of about 1:1 and wherein theparticulating agent is combined with the mixture of lipophilic agent andsolid hydrophilic dispersant in a weight ratio of particulating agent tosaid mixture of about 1:4.
 7. A tablet produced by pressing, at apressure which provides a cohesive tablet, an aliquot of a powdercomprising an admixture of a fast-melting tablet base and a powderproduced by the method according to claim
 6. 8. Solid particulatesformed from constituents at least one of which is in the form of aliquid and comprising a lipophilic liquid, a hydrophilic soliddispersant, and a particulating agent and in which the liquid isdistributed homogeneously throughout the particulates and does not exudetherefrom.
 9. Solid particulates of claim 8 including a bioactivelipophilic liquid.
 10. Solid particulates of claim 8 or 9 where thelipophilic liquid is dispersible from the composition upon contact withan aqueous medium within five minutes.
 11. Solid particulates of claim8, 9 or 10 in the form of a powder.
 12. A powder of claim 11 having aflowability of between about 280 and about 45°.
 13. A tablet comprisingcompressed particulates of any one of claims 8 to
 12. 14. A tabletaccording to claim 13 having a friability of no greater than about 1%.15. A tablet having a friability of no greater than about 1% andcomprising a bioactive lipophilic liquid, a hydrophilic soliddispersant, and a solid particulating agent, wherein said liquid isdispersed uniformly throughout said tablet and is dispersible from saidtablet upon contact with an aqueous medium within one minute.
 16. Atablet of claim 15 wherein the particulating agent is an ingestibleoxide.
 17. A tablet of claim 16 wherein said oxide is silicon dioxide.18. A tablet of claim 15, 16 or 17 in the form of a fast-meltformulation.
 19. A tablet of claim 15, 16 or 17 in the form of achewable formulation.
 20. A tablet of any one of claims 15 to 19 whereinsaid liquid comprises an oil.
 21. A tablet of claim 20 wherein the oilis an essential oil.
 22. A tablet of any one of claims 10 to 16 wherethe dispersant is selected from the group consisting of a sugar, apolyhydroxy alcohol, and a polysaccharide.